The present invention relates to low peak exotherm curable compositions that upon curing are useful as bioadhesives. The compositions of the invention can be placed in contact with one or more skin or mucosal surfaces, or other tissue surfaces, in an initially liquid or malleable form, then subsequently cured or polymerized in place to a final flexible solid or rubbery form.
A broad spectrum of bioadhesives and bioadhesive compositions have been developed, for example, to adhere transdermal patches to the skin and to affix transmucosal patches to mucosal surfaces. In general, the purpose of such bioadhesives is to maintain intimate and prolonged contact with the underlying living tissue surface, in order to allow for the migration of medicinals into the body. In addition, bioadhesive compositions include those that merely adhere a physical barrier, such as a bandage, to living tissue (primarily for the purpose of protecting an underlying wound or compromised tissue surface from potential environmental insults, such as microorganisms). The majority of such bioadhesives are provided as films of varying thicknesses that, upon contact with a biological substrate such as skin or mucosa, display adhesive characteristics suitable for the intended use. For example, a transdermal patch comprises several layers, which may include a protective backing, a drug reservoir and/or matrix, an adhesive layer, and a release film layer. Each layer serves a unique purpose in the delivery of the active drug from the patch to the patient. The adhesive layer provides for the intimate and prolonged contact of the patch with the underlying skin, in order that the active drug may efficiently migrate from the patch reservoir and/or matrix into the skin.
Transmucosal patches are similar in construction, but differ in their adhesion specificity. Since mucosal surfaces (lining of the oral cavity, nasal passages, etc) are relatively moist, effective adhesives generally contain high molecular weight, water-soluble or -swellable polymers that become entangled with tissue surface polymers (such as mucins) upon contact with the moist mucosal surface. Varying the composition of the adhesive layer of the patch can control the strength and duration of contact with the mucosal surface. Transmucosal patches (also known as buccal patches when placed in the oral cavity) can be unidirectional (that is, it releases a drug only in the direction of the mucosal surface to which it is attached) or bidirectional (releases a drug, or other active substance, both in the direction of the mucosal surface, as well as into the rest of the oral cavity). A more thorough review of the subject of bioadhesion to mucosal surfaces can be found in Peppas, N. A. and Sahlin, J. J., Hydrogels as Mucoadhesive and Bioadhesive Materials: A Review, Biomaterials 17 (1996), 1553-1561, which is herein incorporated by reference.
Transdermal and transmucosal patches must also display physical characteristics appropriate to their intended use. Since the underlying biological substrate to which the patches become attached is flexible, patient comfort must be provided for by also formulating and constructing the patches from flexible components. Patch flexibility also allows for movement of the tissue underlying the patch without detachment or separation of the adhesive layer and subsequent loss of the patch.
One drawback of existing transdermal and transmucosal patches is their limited ability to conform to biological substrates that are not relatively flat. For instance, many transdermal patches are adhered to the upper arm, which is a relatively flat surface that provides an easy attachment point for a flat, flexible film patch. However, attachment of such a patch to a more contoured surface, such as on the knuckles of the hand, would be problematical without the ability of the patch to flex and conform in multiple dimensions, especially during movement of the underlying skin.
Transmucosal patches suffer from the same limitations of underlying tissue surface topography, made more difficult by the complexity and difficulty of adhering to a moist substrate, such as the oral mucosa lining the inside of the mouth. For this reason, transmucosal patches are generally small in order to allow them to be placed in a location that may be relatively flat, thus increasing the likelihood of successful, long-term adhesion.
Oral mucosal barrier compositions that are placed in contact with gingival tissue and cured in place to provide a physical barrier against contact of the underlying soft tissue with dental compositions such as tooth bleaching agents and acid etching compositions have been disclosed. Photopolymerizable dental resins have been used for this purpose in the past, generally comprising a curable monomer or blend of monomers (such as bis-GMA and triethyleneglycol dimethacrylate), together with a curing system (such as camphorquinone and dimethylaminomethyl methacrylate). Compositions such as these are described in U.S. Pat. No. 6,048,202 and in WO 98/36700 and are believed to be commercially available from Ultradent Products, Inc (South Jordan, Utah) under the trade name OpalDam(trademark).
Clinical evaluation of OpalDam(trademark) shows poor adhesion to the oral mucosa unless the underlying tissue surface is air-dried and kept free of saliva prior to application of the barrier. In addition, the cured barrier is rigid, which results in frequent detachment of the cured barrier during lengthy dental procedures (such as power bleaching, which employs a heat or light source to assist in the tooth bleaching process). Barrier failure (detachment) can result in contact of the underlying soft tissue with potentially harmful dental agents (such as the high-strength hydrogen peroxide used in tooth bleaching procedures or phosphoric acid, used in acid-etching of tooth surfaces prior to bonding procedures). Yet another disadvantage of OpalDam(trademark) is its high peak exotherm during the curing process. Although temperature detection and pain threshold limits vary from patient to patient, it is generally accepted that most individuals can tolerate temperatures up to about 126xc2x0 F. on the oral mucosa for only short periods of time.
Another disadvantage of currently available dental xe2x80x9cresin damsxe2x80x9d, as they are called, comes from the inclusion of low molecular weight monomers, such as triethylene glycol dimethacrylate, urethane dimethacrylate, and hydroxyethyl methacrylate. Low molecular weight monomers are known skin sensitizers and can penetrate quickly into the oral mucosa both before and after the composition has xe2x80x9ccured.xe2x80x9d See, for example, Hemmer et al., Journal of the. American Academy of Dermatology, 35, 377-380 (1996); Toby et al., Arch. Dermatol. 120, 1202-1205 (1984); Kanerva et al., Contact Dermatitis 37, 255-258 (1997); Kanerva et al., Contact Dermatitis 28, 268-275 (1993); Kanerva et al., Contact Dermatitis 33, 84-89 (1995). Since a typical free radical polymerization of low molecular weight monomers will never proceed to 100 percent completion, there are always residual monomers that do not participate in the polymerization reaction and thus can leach out from the polymerized material to cause unwanted skin reaction and possible health problems.
U.S. Pat. No. 5,900,245 discloses barriers and coatings formed by polymerization of polymerizable materials on the surface of tissue. When formed, these barriers or coatings are compliant with the tissue, as well as adherent, i.e., are capable of conforming to the tissue. In order to attain bioadhesion to the underlying tissue, the compositions described by the inventors must be polymerized from the tissue surface up; that is, a polymerization initiator is first placed on the tissue surface, which is then contacted with a polymerizable composition. When polymerization is initiated, the reaction starts at the tissue surface and progresses through the bulk of the polymerizable composition until the polymerization process is complete. The inventors claim improved adhesive characteristics for their methods and products by process. The inventors do not disclose a means for placing a polymerizable composition on a tissue surface, curing said polymerizable composition in situ, and obtaining a cured, adherent material.
There is a need for compositions that can be placed on a tissue surface in an initial malleable state, allowed to conform well to the underlying tissue, and then subsequently cured to a final flexible bioadhesive. Also, there is a need for a bioadhesive that has excellent bioadhesive qualities and that is flexible. Moreover, there is a need for a curable composition that forms a bioadhesive on a tissue surface upon curing and that does not generate much heat during the curing process, thus providing for patient comfort during the curing process. Finally, there is a need for a bioadhesive that can actively adhere well to both wet and dry tissue surfaces, obviating the need for extensive tissue preparation prior to application.
These and other objectives are achieved by the present invention, which provides low peak exotherm curable compositions which comprise a curable unsaturated compound, a curing agent and an adhesion promoter, and wherein the composition has a peak exotherm of less than about 50xc2x0 C. (120xc2x0 F.).
In one embodiment of the invention, the invention provides a composition which comprises a curable unsaturated compound, a curing agent and an adhesion promoter, wherein curing takes place with a peak exotherm of less than about 50xc2x0 C. (120xc2x0 F.).
In another embodiment of the invention, the invention provides a composition which comprises a curable unsaturated compound and a curing agent and wherein curing takes place with a peak exotherm of less than about 50xc2x0 C. (120xc2x0 F.).
Another embodiment of the invention provides a two part composition which comprises a first part comprising a curable polymerizable compound comprising unsaturated groups, an adhesion promoter and a curing agent, and a second part comprising a curable polymerizable compound comprising unsaturated groups, and a adhesion promoter, and a curing agent synergist of the curing agent of the first part, and wherein upon mixing of the first part and the second part curing takes place with a peak exotherm of less than about 50xc2x0 C. (120xc2x0 F.).
In another embodiment, the invention provides a method for forming a flexible bioadhesive on a tissue, comprising contacting the tissue surface with a composition comprising a curable unsaturated compound, a curing agent and an adhesion promoter, wherein the composition has a peak exotherm during curing of less than about 50xc2x0 C. (120xc2x0 F.), and curing the composition to form the flexible bioadhesive on the tissue.
Another embodiment of the invention is a flexible bioadhesive on a tissue surface prepared by contacting the tissue with a composition of the invention and then curing the composition to form the flexible bioadhesive on the tissue.
The compositions of the invention are (1) curable, i.e., can be transformed from a first liquid, gel, paste, or otherwise shapeable or malleable form to a second solid or otherwise rubbery form, (2) form bioadhesives to the underlying living tissue after curing has occurred, (3) do not generate heat in excess of that which is tolerable by or damaging to the living organism during the curing process, and (4) provide a bioadhesive after curing that is sufficiently flexible to conform to the movements of the underlying living tissue during the period of time which the bioadhesive is in use.